The objective of the proposed research is to establish structural reasons for the general hormonal activity of thyroactive compounds and hypothalamic releasing factors and for the explicit endocrine mechanisms which mediate metabolic and neoplastic processes. It has been shown that hormonal activity of the thyroid and, in particular, the hypothalamic releasing factor TRF, depends primarily on the structure and relative orientations of the various moieties in the molecule. The conclusions drawn from the biological activity and receptor affinity data indicate unique structural requirements for TRF activity and suggest stringent conformational preference for recognition by the receptor. The conformational preference of the thyroid hormones also has become increasingly important with the accumulation of recent evidence which suggests that the hormone triiodothyronine plays a more significant role in biological activity than had been previously supposed. Only with a more detailed understanding of the nature of these hormones at the molecular level, which comes from the quantitative molecular details such as the distances between functional groups, their angular relationships, and the actual size and shape of the molecules, can a full appreciation for their mechanisms of action be obtained. Such information can only be obtained from crystal and molecular structure determination. Therefore it is proposed to determine the exact crystal and molecular structures of a series of thyroactive compounds and hypothalamic releasing factors employing X-ray crystallographic techniques. The molecular architectures of the compounds will be investigated with special emphasis on those structural features which are associated with their biological activities.